1. Field of the Invention
The present invention relates to 2-guanidinylimidazolidinedione compounds, methods of making and purifying 2-guanidinylimidazolidinedione compounds, and methods of using the 2-guanidinylimidazolidinedione compounds to prevent, treat, or inhibit malaria in a subject.
2. Description of the Related Art
The current global situation with respect to malaria indicates that about two billion people are exposed to the disease and of these 400 million people are already infected. See Trigg, P. I., and A. V. Kondrachine (1998) The Current Global Malaria Situation, Chapter 2, p. 11–22, in MALARIA PARASITE BIOLOGY, PATHOGENESIS AND PROTECTION. Ed. I. W. Sherman, ASM Press, Washington, D.C. Each year between 100 to 200 million new cases of infection are reported and approximately 1 to 2 million people die due to malaria. The situation is rapidly worsening mainly due to non-availability of effective drugs and development of drug resistance of a large number of non-immune people in areas where malaria is frequently transmitted. See White, N.J. (1998) Br. Med. Bull. 54:703–715.
WR182393 is a mixture of cyclic dicarboxamide derivatives of chlorproguanil (1), the latter of which is highly active against primary exoerythrocytic forms of
Plasmodium falciparum and P. vivax. See Covell, G. et al. (1949) British Medical Journal 1:88–91; and Curd, F. S. H. et al. (1945) Annals of Tropical Medicine and Parasitology 39:208–216. The compound was synthesized first by Werbel et al. in 1972 and later by Starks Associates Co. by reacting chloroguanil (1) with diethyl oxalate (2)
according to the following Scheme 1:

Recently, WR182393 was found to possess prophylactic activity in the mouse Rane assay comparable to that of tafenoquine when administered subcutaneously. In the Rane mouse prophylactic assay, WR182393 demonstrated radical cure by subcutaneous administration at 10 mg/kg and at higher doses of 160 mg/kg by oral. See Corcoran, K D, et al. (1993) Am. J. Trop. Med. Hyg. 49:473–477, and Shanks, G D, et al. (2001) Clinical Infectious Diseases 33:1968–1974. In Rhesus monkeys, WR182393 also demonstrated both radical curative and causal prophylactic activity against P. cynomolgi when given i.m. Thus, the active component of WR182393 is potentially a valuable lead for drug discovery of a causal prophylactic drug for prevention of falciparum malaria.
Due to poor solubility of the products in water or organic solvents, the purification of the reaction mixture is very difficult. The structure of the reaction product was assumed by the manufacture to be compound 3.

However, there was no analytical data to support this contention. Because of the poor solubility, small-scale purification of the mixture is very difficult and large-scale purification is almost impossible. Consequently, the structure determination of the components of WR182393 mixtures has been a frustrating task of medicinal chemists.
Therefore, a need still exists for methods for making and purifying the active compounds of WR182393 and compositions thereof that may be used for treating, preventing, or inhibiting malaria.